The present invention relates to a therapeutic or prophylactic agent for glomerulonephritis, lupus nephritis, idiopathic thrombocytopenic purpura or autoimmune anemia, which comprises a retinoic acid receptor (RAR) agonist as an active ingredient. In particular, the present invention relates to a therapeutic or prophylactic agent for systemic erythematosus, glomerulonephritis, lupus nephritis, idiopathic thrombocytopenic purpura or autoimmune anemia, which comprises a retinoic acid receptor subtype xcex1 (RARxcex1) agonist as an active ingredient.
1) Glomerulonephritis
Glomerulonephritis is generally called nephritis where continuous albuminuria and hematuria are clinically observed, and shows a morbid state in which renal functional disturbance and complications of edema, high blood pressure and cardiac insufficiency due to storage of sodium occur in some cases.
Pathogenically, glomerulonephritis can be defined as a glomerular disease showing an increase in mesangium (phonetic transcription) cells and/or substrate in renal glomeruli.
The most universal idea on the mechanism of the onset of glomerulonephritis is that immune reaction products occurring on glomeruli damage the glomeruli. It is also evident from the fact that the damage is caused by heteroantibody and host antibody in an animal experiment. Masugi experimentally created glomerulonephritis by intravenously administering duck-derived nephrotoxic serum against rabbit renal tissues into normal domestic rabbits, and domestic rabbit-derived nephrotoxic serum against rat renal tissues into rats, thus demonstrating that glomerulonephritis is generated by an immunological mechanism (Masugi, M., Beitr. Pathol. Anat., 91, 82-112, 1933, Masugi, M., Beitr. Pathol. Anat., 92, 429-466, 1934). Since fluorescent antibody techniques were introduced for renal materials in biopsy in the 1960""s, there have been reported a large number of data suggesting that an immunological mechanism is involved in generating glomerulonephritis in humans as well. In nephritis caused by these immune reactions, sedimentation of an antigen-antibody immune complex (IC) onto glomeruli is particularly important.
From the previous results of studies on animal experiment models, nephritis caused by precipitation of IC in circulating blood and nephritis by formation of IC in situ are being considered. The former is nephritis caused by binding a protein antigen originally unrelated to glomerular tissues to its corresponding antibody in blood, to form IC which is then precipitated on a glomerular sling wall or on mesangium. The latter includes 2 types of nephritis: one is caused by IC formed by binding an antibody against a renal tissue antigen (unique component in glomerular basement membrane and glomerular cells) directly to glomeruli, and the other is caused by IC formed by precipitation of an extraneous antigen via electrical charge or other affinity on glomeruli and subsequent binding of its corresponding antibody to the glomeruli in situ. The site on which IC is precipitated includes mesangium observed in endothelial cells and IgA nephropathy, in addition to epithelial cells observed in human nephropathy originating in membrane. The factors determining the precipitation site include the size of immune complex, the electric charge of antigen, antibody and immune complex, the binding force between antigen and antibody, and type and subclass of antibody. These factors are involved in precipitating an immune complex in blood or forming an immune complex in situ followed by activation of complements to initiate inflammation reaction.
Major therapeutic agents used at present for glomerulus nephritis include anti-platelet agents, anti-coagulating agents, adrenocortical steroids and immunosuppressive agents. Among these, as described above, the immunological mechanism is involved considerably in the onset of nephritis so that conventional therapy for nephritis is based on adrenocortical steroids inhibiting immune response.
The nephrosis syndrome is a disease to which adrenocorticotrophic steroids are most suited. However, the glomerulus nephritis as a causative disease for the nephrosis syndrome has various types ranging from the primary to secondary one, thus revealing that thereactivity of steroids to the nephritis syndrome is varied depending on the type of nephritis. For example, the complete remission of minimal change nephrotic syndrome (MCNS) is achieved in 80 to 95% cases by steroids. However, the effect of therapy with steroid is hardly expected except for only the case of IgA nephropathy where the degree of albuminuria is moderate while renal function is maintained, and in only this case, the therapy with steroid is performed. About ⅔ of patients with acute nest-like glomerular sclerosis respond to steroids, but the other ⅓ patients are resistant to steroids and advance to terminal-stage renal insufficiency, and patients with chronic glomerular sclerosis are also hardly responsive to steroids. Although a reduction in albuminuria in nephropathy originating in membrane (glomerulonephritis originating in membrane) is recognized by use of steroids for aprolonged period of time, stringent evaluation of this therapy is still not be established. Further, secondary lupus nephritis is classified into I to IV types in renal biopsy, and the clinical effect of the steroids thereon is varied; the effect on the IV type (diffuse proliferation type) cannot be expected even by administering in a large amount, rather there is the possibility of aggravation.
An immunosuppressive agent is used in combination when therapy using only adrenocortical steroid is insufficient in the case of steroid-resistant and frequently relapsing nephrosis syndrome, rapidly progressive glomerulonephritis or lupus nephritis, or for the purpose of reducing the dose of the adrenocortical steroid. Generally used agents include cyclophosphamide, cyclosporin A and mizoribine. Cyclophosphamide is used frequently, but there occur various side effects depending on the dose. Major side effects include bone marrow inhibition, hepatic damage, alopecia, lung fibrosis, bleeding cystitis and hypofunction of sexual glands. Cyclosporin A shows an immunosuppressive action on T cells, but it has severe side effects include renal damage, hepatic damage, central nerve damage, infections and acute pancreatitis, among which the renal damage occurs depending on the blood concentration, thus making it necessary to monitor the blood concentration. Mizoribine has less side effects than other immunosuppressive agents, but is poor in effect on the diseases.
As described above, there are a large number of cases where the effects of the adrenocortical steroids used as the first choice in conventional therapy are not satisfactory, while the immunosuppressive agents used for compensating therefor have the problem of side effects.
2) Autoimmune Diseases in which Autoantibody is Involved
The autoantibody observed in autoimmune diseases is roughly divided into 2 groups depending on the characteristic distribution of its corresponding antigen in the body. The first group is an organ-specific autoantibody observed in organ-specific autoimmune diseases. This kind of autoantibody corresponds to anti-thyroid-stimulating hormone receptor antibody detected in patients with Basedow""s disease, or to an anti-acetyl choline receptor antibody detected in patients with severe myasthenia. The second group is the one which reacts with antigen present in almost all organs in the body or in serum, and is called organ-unspecific autoantibody. The characteristic autoantibody in systematic autoimmune diseases such as glycogen storage disease is included in this group. These autoimmune antibodies directly damage organs or form an immune complex thereby generating the morbid state of autoimmune diseases. Further, even in autoimmune diseases wherein the relationship between the presence of autoantibody and the morbid state is not clear, the detection of autoantibody is revealed to be clinically important as being indicative of diagnosis, activity of the diseases, and judgement of therapeutic effect. Hereinafter, some typical autoimmune diseases in which autoantibody is involved are described.
Systemic lupus erythematosus (SLE) shows various symptoms, and symptoms and examination views adopted as classification criteria includes the following 11 items: 1) cheek erythema, 2) disk-shaped erythema, 3) hypersensitivity to light, 4) ulcer in the oral cavity, 5) arthritis, 6) serositis, 7) renal damage, 8) nerve damage, 9) blood abnormality, 10) immune abnormality, and 11) antinuclear antibody. These symptoms and abnormalities in examination are considered due to autoantibody. It is estimated that antinuclear antibody as typical autoantibody forms an immune complex and causes disturbance such as lupus nephritis via the III type allergy mechanism. Lupus nephritis is observed in 60% of patients with systematic erythematosus, and for the treatment, adrenocortical steroids are used. However, in the case of steroid-resistant lupus nephritis or when there occur severe side effects of steroids, administration of an immunosuppressive agent is taken into consideration. An immunosuppressive agent used frequently is azathiopurine or cyclophosphamide.
Idiopathic thrombocytopenic purpura (ITP) is a disease in which autoantibody against platelets is produced to destroy platelets. Clinical symptoms include the tendency of bleeding caused by a reduction in platelets, and bleeding occurs mainly under the skin and on the mucosa to cause purpura, petechia and blood spot. When platelets are significantly reduced, there occur complications of oral bleeding, nasal bleeding, genital bleeding, bloody excrements, retinal hemorrhage etc., and the most severe case, the complications are accompanied by cranial hemorrhage. For general treatment of ITP, an adrenocortical steroid is used as a first choice, followed by conducting pancreatectomy. However, there are not few cases showing resistance to this standard treatment, and in these cases, treatment by administration of an immunosuppressive agent or danazole is attempted, but the effectiveness is not so high.
In autoimmune hemolytic anemia, antibody against self-erythrocytes is produced to cause hemolysis, and anemia and jaundice are clinically observed. Treatment is based on administration of steroids, and an immunosuppressive agent is also used if response is poor, or to reduce maintenance dose of steroids. However, it was recognized that about xc2xc of the patients are worsened during maintenance therapy.
In Basedow""s disease, autoantibody against thyroid-stimulating hormone receptors stimulates the thyroid to cause hyperthyroidism. As clinical symptoms, diffuse struma, tachycardia, tremor of fingers are observed. For treatment, the inhibition of formation of the hormone by administering an anti-thyroid drug such as thiamazole or propyl thiouracil, by destruction of the thyroid gland with radioactive iodine, or by subtotal resection of the thyroid gland by operation is performed, but there is no established therapeutic method against the causative factor of the disease.
Accordingly, the object of the present invention is to provide a therapeutic or prophylactic agent as a substitute for conventional steroids or immunosuppressive agents to treat systemic erythematosus, glomerulonephritis, lupus nephritis, idiopathic thrombocytopenic purpura or autoimmune anemia.
Retinoic acid plays an important role for growth of animal and in maintaining functions, such as specific regulation of differentiation and proliferation of cells and morphological formation of vertebrates. In connection with these physiological actions, retinoic acid attracts attention as an anticancer agent or as a specific remedy for proliferated skin diseases (psoriasis and keratosis), and a number of retinoic acid analogues have been synthesized. In recent years, the presence of xcex1, xcex2 and xcex3 subtypes of retinoic acid receptor was revealed (The Retinoids, 2nd ed., Raven Press, Ltd., New York, 1994, Sporn, M. B., Roberts, A. B., Goodman, D. S.). However, the physiological importance of each receptor has not been revealed yet.
On the other hand, the intimate involvement of vitamin A in the immune system has been known from of old. There are many reports in which retinoic acid as a product of metabolism of vitamin A acts for inhibition of the immune system. For example, Brinckerhoff et al. have reported that secondary inflammations in rat adjuvant arthritis as a model with human rheumatic arthritis are significantly suppressed by administering 13-cis-retinoic acid (Brinckerhoff, C. E., et al., Science 221, 756, 1983). Further, Racke et al. have reported that neural symptoms of mouse allergic cerebrospinal meningitis as a model with human multiple sclerosis is ameliorated by administering retinoids such as 13-cis-retinoic acid and 4-hydroxyretinamide (Racke, M. K., et al., J. Immunol., 154, 450-458, 1995). It is suggested that in these models, retinoids ameliorate the morbid state by inhibiting the activation of T-lymphocytes.
In addition, it is also reported that retinoids inhibit the activation of B lymphocytes. That is, it is reported that all-trans-retinoic acid inhibits polyclonal division of mouse B lymphocytes or human B lymphocytes (Apfel, C., Proc. Natl. Acad. Sci. USA, 89, 7129-7133, 1992, Blomhoff, H. K., et al., J. Biol. Chem., 25, 23988-23992, 1992 and Fahlman, C., et al., J. Immunol., 155, 58-65, 1995). Further, it is reported that Am80 which is a retinoic acid receptor subtype xcex1 (RARxcex1) agonist strongly inhibited production of anti-collagen antibody titer in blood in a rat model with collagen arthritis (Kuwabara, K., et al., FEBS Letters, 378, 153-156, 1996).
It is shown that retinoids act on B lymphocyte via retinoic acid receptor (RAR) (Blomhoff, H. K., et al., J. Cell. Physiol., 175, 68-77, 1998). Further, it is suggested that RARxcex1 has an important role in demonstrating the actions described above, from the following findings: (1) among RAR subtypes, RARxcex1 and RARxcex3 are expressed in human B lymphocytes, and in particular RARxcex1 is strongly expressed, while RARxcex2 is not expressed (Blomhoff, H. K., et al. 1998, supra, and Buck, J. L., et al., J. Cell. Biol., 115, 851-859, 1991) and (2) the inhibitory action of retinoic acid on differentiation of mouse B lymphocytes was recovered almost perfectly by adding RARxcex1 antagonist (Ro 41-5253) (Apfel, C., 1992, supra).
As described above, retinoids inhibit the activation of B lymphocytes in addition to T lymphocytes, and this effect is suggested to be via RARxcex1 in particular among the RAR subtypes. However, even the reports mentioned above do not contain any description indicating a clear relationship between RAR or RARxcex1 and production of antibody by B lymphocytes.
WO94/17796, U.S. Pat. No. 4,703,110, JP-A 2-76862, JP-A 63-255277, JP-A 8-505359, WO97/24116 etc. disclose the use of retinoid-like active compounds for treating a wide variety of inflammatory, allergic and rheumatic immune diseases including cancers such as leukemia, breast cancer, prostate cancer, lung cancer, esophagus and respiratory tract cancer, skin cancer and bladder cancer; skin diseases such as psoriasis, keratosis, eczema, atopic dermatitis, acne and Darier""s disease; autoimmune diseases such as chronic articular rheumatism and erythematosus; chronic polyarthritis, spinal arthritis and deformable arthritis. However, these publications neither suggest a therapeutic method against specific causative factors, for example by utilizing the inhibitory action of RAR agonist on production of autoantibody to treat autoimmune diseases in which the autoantibody is involved, nor contain any description of glomerulonephritis, lupus nephritis, idiopathic thrombocytopenic purpura and autoimmune anemia. However, in only WO97/34869 there appears a description of glomerulonephritis, but there is no disclosure on specific data suggesting or clearly showing the effect, nor is there a description of lupus nephritis, idiopathic thrombocytopenic purpura and autoimmune anemia. Further, there is none of the description that among RAR agonists, subtype xcex1-agonist contributes particularly to prevention and treatment of systematic erythematosus and glomerulus nephritis.
The present inventors extensively studied retinoid compounds and found that RAR agonists have potent inhibitory action on production of antibody. On the basis of this finding, they further continued the study to find that among a plurality of subtype receptors, particularly RARxcex1 agonist acting on xcex1-receptor is a major agonist contributing to the inhibitory action, thus completing the present invention.
The present invention relates to a therapeutic or prophylactic agent for a disease against which the inhibitory action of a retinoic acid receptor (RAR) agonist or a pharmacologically acceptable salt thereof as an active ingredient on production of antibody is effective. Further, the present invention relates to use of a retinoic acid receptor (RAR) agonist or a pharmacologically acceptable salt thereof for producing a therapeutic or prophylactic agent for a disease against which the inhibitory action thereof on production of antibody is effective.
That is, the present invention relates to a therapeutic or prophylactic agent for systematic erythematosus, glomerulonephritis, lupus nephritis, idiopathic thrombocytopenic purpura or autoimmune anemia, wherein a retinoic acid receptor (RAR) agonist, particularly an RARxcex1 agonist or a pharmacologically acceptable salt thereof, comprising compounds shown (1) to (12) below, is used as an active ingredient.
1) carboxylic acid compounds having condensed rings represented by the formula (I): 
xe2x80x83wherein the rings L and M are condensed, are the same as or different from each other and represent an aromatic hydrocarbon which may have a substituent group or a heterocycle which may have a substituent group, the rings A and B are independent of each other and represent an aromatic hydrocarbon ring or heterocycle which may have a substituent group, and D is a carboxyl group which may have a protective group,
2) carboxylic acid compounds having heterocycle disclosed in JP-A 9-71566, which are represented by the formula (II): 
wherein A represents the following groups: 
xe2x80x83(wherein R1 to R3, R18 to R28 and R30 to R36 are the same as or different from and represent hydrogen atom, a halogen atom, a lower alkyl group or a phenyl group which may have a substituent group, and the formula xe2x80x94xe2x80x94xe2x80x94xe2x80x94xe2x80x94 represents a single or double bond),
B represents a heteroarylene group which may have a substituent group, an arylene group which may have a substituent group, the group represented by the formula xe2x80x94CONHxe2x80x94 or the group represented by the formula xe2x80x94CR6xe2x95x90CR7xe2x80x94 (wherein R6 and R7 are the same as or different from each other and represent hydrogen atom, a lower alkyl group or a halogen atom),
D represents an arylene group which may have a substituent group, a heteroarylene group which may have a substituent group or the group represented by the formula xe2x80x94CR6xe2x95x90CR7 (wherein R6 and R7 have the same meanings as defined above), n1 is 0 or 1, and
M represents hydroxyl group, a lower alkoxy group or the group represented by the formula xe2x80x94NR16R17 (wherein R16 and R17 are the same as or different from each other and represent hydrogen atom, hydroxyl group, a lower alkyl group, a hydroxyalkyl group, an aryl group or a heteroaryl group, or R16 and R17 may, together with a nitrogen atom to which they are bound, form a ring optionally containing an oxygen or sulfur atom,
3) 4-{2-[5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)pyrrolyl]}benzoic acid, 4-{2-[5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)franyl]}benzoic acid, 4-{2-[5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)thiophenyl]}benzoic acid or 4-{2-[5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)pyrazolyl]}benzoic acid disclosed in JP-A 2-240058,
4) 4-[2-(3,4-dihydro-2H-1-benzopyran-6 or 7-yl)propenyl]benzoic acid compounds, 4-[2-(3,4-dihydro-2H-1-benzothiopyran-6 or 7-yl)propenyl]benzoic acid compounds, 4-[2-(1,2,3,4-tetrahydroquinoline-6 or 7-yl)propenyl]benzoic acid compounds, 4-{[(3,4-dihydro-2H-1-benzopyran-6 or 7-yl)carbonyl]amino}benzoic acid compounds, 4-{[(3,4-dihydro-2H-1-benzothiopyran-6 or 7-yl)carbonyl]amino}benzoic acid compounds or 4-{[(1,2,3,4-tetrahydroquinoline-6 or 7-yl)carbonyl]amino}benzoic acid compounds disclosed in JP-A 2-76862,
5) 4-(trimethylsilyl-substituted phenyl)benzoic acid compounds disclosed in JP-A 1-249783,
6) [(3,4-dihydro-2H-1-benzopyran-6-yl)ethynyl]heteroaryl carboxylic acid compounds, [(3,4-dihydro-2H-1-benzothiopyran-6-yl)ethynyl]heteroaryl carboxylic acid compounds or [(1,2,3,4-tetrahydroquinoline-6-yl)ethynyl]heteroaryl carboxylic acid compounds disclosed in JP-A 63-255277,
7) (E)-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenol compounds disclosed in JP-A 62-267245,
8) 4-{[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]amino}benzoic acid compounds disclosed in JP-A 61-22047,
9) 9-(substituted phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraene-1-one acid compounds disclosed in JP-A 49-126637,
10) all-trans-retinoic acid,
11) 4-{2-[5-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl)pyrrolyl]}benzoic acid or 4-{2-[5-(3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)pyrrolyl]}benzoic acid, and
12) 4-{[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)carbonyl]amino}benzoic acid compounds, 4-{[(2,2,4,4-tetramethylchroman-2-yl)carbonyl]amino}benzoic acid compounds or 4-{[(2,6-di-t-butylpyrido-4-yl)carbonyl]amino}benzoic acid compounds disclosed in WO97/24116.
In the present invention, preferable compounds include: all-trans-retinoic acid; 4-{[(3,5-bistrimethylsilylphenyl)carbonyl]amino}benzoic acid compounds disclosed in JP-A 1-249783; 4-{[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]amino}benzoic acid or 4-{[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)amino]carbonyl}benzoic acid disclosed in JP-A 61-22047; and the compound group represented by the following general formula: 
wherein L, M, A, B and D have the same meanings as defined above, 
wherein A, B, D, M and n1 have the same meanings as defined above.
More preferable compounds are the compound group shown in (1) to (20) below:
(1) 4-{2-[5-(5,8-dimethylnaphthalene-2-yl)pyrrolyl]}benzoic acid, (2) 4-{2-[5-(8-methylnaphthalene-2-yl)pyrrolyl]}benzoic acid, (3) 4-{2-[5-(8-ethylnaphthalene-2-yl)pyrrolyl]}benzoic acid, (4) 4-{2-[5-(8-isopropylnaphthalene-2-yl)pyrrolyl]}benzoic acid, (5) 4-{2-[5-(8-isopropenylnaphthalene-2-yl)pyrrolyl]}benzoic acid, (6) 4-{2-[5-(8-penylnaphthalene-2-yl)pyrrolyl]}benzoic acid, (7) 4-{2-[5-(4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid, (8) 4-{2-[5-(4,7-dichlorobenzofuran-2-yl)pyrrolyl]}benzoic acid, (9) 4-{2-[5-(5-chloro-7-ethylbenzofuran-2-yl)pyrrolyl]}benzoic acid, (10) 4-{2-[5-(4,7-dimethylbenzothiophene-2-yl)pyrrolyl]}benzoic acid, (11) 4-{2-[5-(3-fluoro-4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid, (12) 4-{2-[5-(7-ethyl-4-methylbenzofuran-2-yl)pyrrolyl]}benzoic acid, (13) 4-{2-[5-(7-fluoro-4-trifluoromethylbenzofuran-2-yl)pyrrolyl]}benzoic acid, (14) 4-{2-{5-[3-(1-ethyl-5-isopropylpyrazolyl)]pyrrolyl}}benzoic acid, (15) 4-{2-{5-[7-(1,5-dimethyl-2,3,4,5-tetrahydro-1H-benzazepinyl}pyrrolyl}benzoic acid, (16) 4-{4-{2-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalynyl)]furyl}}benzoic acid, (17) 4-{2-{5-[2-(8,8-dimethyl-5,6,7,8-tetrahydroquinoxalynyl)]pyrrolyl}}benzoic acid, (18) 4-{[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)amino]carbonyl}benzoic acid, (19) 4-{[(3,5-bistrimethylsilylphenyl)carbonyl]amino}benzoic acid and (20) 4-{2-[5-(3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)pyrrolyl]}benzoic acid.
In the present invention, the term xe2x80x9cmay have a substituent groupxe2x80x9d means that the group may be substituted by the group selected from hydroxyl group; thiol group; nitro group; cyano group; halogen atom such as fluorine atom, chlorine atom, bromine atom and iodine atom; lower alkyl group such as methyl, ethyl, n-propyl and isopropyl; lower alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy and butoxy group; halogenated alkyl group such as fluoromethyl group, difluoromethyl group, trifluoromethyl group and 2,2,2-trifluoroethyl group; alkylthio group such as methylthio group, ethylthio group and isopropylthio group; acyl group such as acetyl group, propionyl group and benzoyl group; hydroxyalkyl group such as hydroxymethyl group, hydroxyethyl group and hydroxypropyl group; amino group; monoalkyl amino group such as methyl amino group, ethyl amino group and isopropyl amino group; dialkyl amino group such as dimethyl amino group and diethyl amino group; carboxyl group; alkoxy carbonyl group such as methoxy carbonyl group, ethoxy carbonyl group and propyl carbonyl group; carbamoyl group; alkyl carbamoyl group such as methyl carbamoyl group and dimethyl carbamoyl group; acyl amino group such as acetyl amino group and benzoyl amino group; alkyl sulfonyl group such as sulfamoyl group, methyl sulfonyl group and ethyl sulfonyl group; unsubstituted or substituted aryl sulfonyl group such as benzene sulfonyl group and p-toluene sulfonyl group; unsubstituted or substituted aryl group such as phenyl group, tolyl group and anisolyl group; unsubstituted or substituted heteroaryl group such as pyrrole group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, thiazolyl group, pyridyl group, pyrimidyl group and pyrazinyl group; carboxy alkyl group; alkyloxycarbonyl alkyl group such as methoxycarbonyl methyl group, ethoxycarbonyl methyl group and methoxycarbonyl ethyl group; carboxyalkoxy group such as carboxymethoxy group; aryl alkyl group such as benzyl group and 4-chlorobenzyl group; heteroaryl alkyl group such as pyridyl methyl group and pyridyl ethyl group; and alkylene dioxy group such as methylene dioxy group and ethylene dioxy group.
The aromatic hydrocarbon means benzene, naphthalene, anthracene etc.
The heterocycle means a group derived from a monocyclic ring containing 1 to 3 atoms of at least one member selected from the group consisting of sulfur atom, oxygen atom and nitrogen atom. For example, it means a pyrrole ring, thiophene ring, furan ring, thiazole ring, oxazole ring, isothiazole ring, isoxazole ring, imidazole ring, pyrazole ring, thiadiazole ring, oxadiazole ring, triazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring etc.
The halogen atom means a fluorine atom, chlorine atom and iodine atom.
The lower alkyl group means a C1 to C6 linear or branched alkyl group such as methyl group, ethyl group, n-propyl group, n-butyl group, isopropyl group, isobutyl group and n-hexyl group.
The arylene group means the above aromatic hydrocarbon group having two bonds available for bonding.
The heteroarylene group means the above heterocyclic group having two bonds available for bonding.
The compound of formula (I) can be obtained easily by an ordinarily used method or a combination of ordinarily used methods. One example is as follows:
The compound wherein ring A is a pyrrole ring can be obtained in the following method. 
(Step 1)
In this reaction, the aldehyde (1) is reacted in a usual manner with an organometallic reagent to give the allyl alcohol (2).
The organometallic reagent includes e.g. a Grignard reagent, an organic lithium reagent, an organic zinc reagent and an organic copper complex. In the presence of a catalytic amount of copper iodide, the desired product can be produced in higher yield. The reaction solvent maybe any solvents which is inert to the reaction, and preferable examples include ether solvents such as ether and tetrahydrofuran. The reaction temperature is in the range of about xe2x88x9278xc2x0 C. to the boiling point of the solvent, and preferably about xe2x88x9278xc2x0 C. to 20xc2x0 C.
(Step 2)
In this step, the allyl alcohol (2) obtained in step 1 is oxidized in a conventional manner to give the vinyl ketone (3).
The oxidation may be conducted in any ordinarily used methods, preferably using a suitable oxidizing agent. The examples of oxidizing agent used include activated manganese dioxide, chlorochromate pyridium, dichromate pyridium, a Dess-Martin reagent, a Swern oxidizing agent, TEMPO (sodium 2,2,6,6-tetramethyl-1-piperidinyloxy hypochlorite)-copper chloride, TEMPO-NaOCl etc. The reaction solvent may be any solvents which is inert to the reaction, and preferable examples include dichloromethane, chloroform, acetone etc. The reaction temperature is in the range of about xe2x88x9278xc2x0 C. to the boiling point of the solvent, and preferably about xe2x88x9278xc2x0 C. to 20xc2x0 C.
(Step 3)
In this step, the diketone compound shown in the formula (5) is obtained by the method of Stetter 5 described in Org. Synth. 65, 26 by use of the vinyl ketone (3) obtained in step 2 and the aldehyde (4).
In this reaction, use of a thiazolium salt catalyst brings preferable results. For this reaction, a base such as triethylamine and sodium acetate is preferably used. A reaction solvent such as methanol, ethanol, N,N-dimethylformamide, etc. is used. The reaction temperature is preferably about 60xc2x0 C. to the boiling point of the solvent.
(Step 4)
In this step, the diketone (5) obtained in step 3 is treated in a usual manner to give the pyrrole compound represented by the formula (6).
For example, by the reaction with an ammonium salt such as ammonium acetate or with a primary amine, the desired compound (6) can be obtained. In this case, an alcohol solvent such as methanol and ethanol, acetic acid or the like is used as the reaction solvent. The reaction temperature is preferably about 70xc2x0 C. to the boiling point of the solvent.
The pyrrole (6) obtained in step 4 is hydrolyzed in a usual manner whereby its corresponding carboxylic acid compound can be obtained. In this case, use of a base brings good results. As the base, an aqueous solution of lithium hydroxide, sodium hydroxide, potassium hydroxide or the like gives rise to good results. The reaction solvent is preferably alcohol solvent such as methanol and ethanol or ether solvent such as tetrahydrofuran. The reaction temperature is preferably about 20xc2x0 C. to the boiling point of the solvent.
Processes for producing the other compound group are disclosed in JP-A 9-71566, JP-A 2-240058, JP-A 2-768.62, JP-A 1-249783, JP-A 63-255277, JP-A 61-22047, and WO97/24116.
The compounds of the present invention are administered orally or parenterally. The compound group of the present invention can be administered in forms such as tablets, powder, granulates, capsules, syrups, troches, suppositories, injections, intravenous drip infusions, ointments, nasal drops, poultices and lotions.
The dose varies depending on the severeness of symptoms, the age, sex, weight and sensitivity of the patient, the administration method, administration time, administration intervals, the properties of the pharmaceutical preparation used, and its active ingredient, and there is no particular limit to the dose. Usually, the daily dose for an adult is 0.1 to 2000 mg, preferably 0.1 to 1000 mg. Usually this daily dose is administered in one portion or in divided portions. When administered in the form of an injection, usually 1 to 1000 xcexcg/kg, preferably 1 to 300 xcexcg/kg is administered.